Hanold Laura E, Watkins Christopher P, Ton Norman T, Liaw Peter, Beedle Aaron M, Kennedy Eileen J
Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA.
Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, 240 W. Green St., Athens, GA 30602, USA.
Bioorg Med Chem. 2015 Jun 15;23(12):2761-6. doi: 10.1016/j.bmc.2015.03.040. Epub 2015 Mar 20.
The epidermal growth factor receptor (EGFR) dimerization arm is a key feature that stabilizes dimerization of the extracellular receptor, thereby mediating activation of the tyrosine kinase domain. Peptides mimicking this β-loop feature can disrupt dimer formation and kinase activation, yet these peptides lack structural constraints or contain redox sensitive disulfide bonds which may limit their stability in physiological environments. Selenylsulfide bonds are a promising alternative to disulfide bonds as they maintain much of the same structural and chemical behavior, yet they are inherently less prone to reduction. Herein, we describe the synthesis, stability and activity of selenylsulfide-bridged dimerization arm mimics. The synthesis was accomplished using an Fmoc-based strategy along with C-terminal labeling for improved overall yield. This selenylsulfide-bridged peptide displayed both proteolytic stability and structural stability even under reducing conditions, demonstrating the potential application of the selenylsulfide bond to generate redox stable β-loop peptides for disruption of protein-protein interactions.
表皮生长因子受体（EGFR）二聚化臂是稳定细胞外受体二聚化的关键特征，从而介导酪氨酸激酶结构域的激活。模拟这种β-环特征的肽可以破坏二聚体形成和激酶激活，但这些肽缺乏结构限制或含有氧化还原敏感的二硫键，这可能会限制它们在生理环境中的稳定性。硒硫键是二硫键的一种有前途的替代物，因为它们保持了许多相同的结构和化学行为，但它们天生不易被还原。在此，我们描述了硒硫键桥连的二聚化臂模拟物的合成、稳定性和活性。合成采用基于Fmoc的策略以及C端标记以提高总产率。这种硒硫键桥连的肽即使在还原条件下也表现出蛋白水解稳定性和结构稳定性，证明了硒硫键在生成用于破坏蛋白质-蛋白质相互作用的氧化还原稳定的β-环肽方面的潜在应用。
